Substituted tetrahydronaphthalenes, method for the production thereof, and use thereof as drugs

1. A compound of the formula I

in which

R1

is H, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1-4 -C 4 )-alkyl, (C 3 -C 8 )-alkenyl, (C 3 -C 8 )-alkynyl, CO(R9), (C(R10)(R11)) q -R12, CO(C(R13)(R14)) r -R15, CO—O(C 1 -C 8 )-alkyl, or CO(C(R13)(R14)) r -N(R16)(R17);

R2

is H, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 3 -C 8 )-alkenyl, (C 3 -C 8 )-alkynyl, CO(R9), (C(R10)(R11)) q -R12, CO(C(R13)(R14)) r -R15, CO—O(C 1 -C 8 )-alkyl, or CO(C(R13)(R14)) r -N(R16)(R17);

or

R1 and R2, together with the nitrogen atom to which they are bonded, form a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, optionally including 0 to 3 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system is optionally substituted by F, Cl, Br, CF 3 , CN, (C 1 -C 6 )-alkyl, (C 3 -C 8 )-cycloalkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 6 )-alkyl, oxo, CO(R18), CON(R19)(R20), hydroxyl, COO(R21), N(R22)CO(C 1 -C 6 )-alkyl, N(R23)(R24) or SO 2 (C 1 -C 6 )-alkyl;

R10 and R11

are each independently H, (C 1 -C 6 )-alkyl, hydroxy-(C 1 -C 2 )-alkyl, F or OH;

R9, R13, R14, R16, R17, R18, R19, R20, R21, R22, R23, and R24

are each independently H or (C 1 -C 6 )-alkyl;

or

R16 and R17, R23 and R24

each independently form, together with the nitrogen atom to which they are bonded, a 5-6-membered ring which, apart from the nitrogen atom, optionally including 0-1 further heteroatom from the group of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;

q and r are each independently 0, 1, 2, 3, 4, 5, or 6;

R12 and R15

are each independently H, OH, F, O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 )-alkyl, CN, COO(R25), N(R26)CO(C 1 -C 6 )-alkyl, N(R27)(R28), CON(R29)(R30), SO 2 (C 1 -C 6 )-alkyl, or a 3-12-membered mono-, bi- or spirocyclic ring which may contain one to four heteroatoms from the group of N, O and S, and the 3-12-membered ring optionally containing further substituents selected from F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , oxo, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, O—(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, O—(C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, N(R31)(R32), COO(R33), SO 2 (C 1 -C 6 )-alkyl and COOH;

R25, R26, R27, R28, R29, R30, R31, R32, and R33

are each independently H or (C 1 -C 6 )-alkyl;

or

R27 and R28, R29 and R30, R31 and R32

each independently form, together with the nitrogen atom to which they are bonded, a 5-6-membered ring which, apart from the nitrogen atom, optionally including 0-1 further heteroatom from the group of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;

L1 is C(R34)(R35), C(R36)(R37)C(R38)(R39) or (C 3 -C 6 )-cycloalkyl;

R1 may optionally be joined to one of the R34, R35, R36, R37, R38 or R39 radicals, so as to form a 5-6-membered ring optionally substituted in the carbon chain by (C 1 -C 6 )-alkyl;

R34, R35, R36, R37, R38, and R39

are each independently H or (C 1 -C 6 )-alkyl;

R3, R4, and R5

are each independently H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 -alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, CON(R40)(R41) or CO(R42);

R40, R41, and R42

are each independently H or (C 1 -C 6 )-alkyl;

Or

R40 and R41

form, together with the nitrogen atom to which they are bonded, a 5-6-membered ring which, apart from the nitrogen atom, optionally including 0-1 further heteroatom from the group of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;

X is C(R7″)(R7″′);

R6, R6′, R7, R7′, R7″, and R7″′

are each independently H, F, (C 1 -C 6 )-alkyl, OH, or O—(C 1 -C 6 )-alkyl;

R8 is H or (C 1 -C 6 )-alkyl;

A is a 5-6-membered aromatic ring optionally including up to 2 heteroatoms selected from the group of nitrogen, oxygen and sulfur, and optionally substituted by one or more of the substituents H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 -alkyl, N(R43)(R44), SO 2 —CH 3 , CON(R45)(R46), N(R47)CO(R48), and CO(R49);

R43, R44, R45, R46, R47, R48, and R49

are each independently H or (C 1 -C 6 )-alkyl;

or

R43 and R44, R45 and R46

each independently form, together with the nitrogen atom to which they are bonded, a 5-6-membered ring which, apart from the nitrogen atom, optionally including 0-1 further heteroatom from the group of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;

L2 is a bond or a linker having 1 to 4 members, where the members are selected from the group consisting of 0, S, SO 2 , N(R50), CO, C(R51)(R52), and C≡C, and the linker does not have any O—CO or COO groups;

B is (C 1 -C 6 )-alkyl, CF 3 , (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 6 )-alkyl or a 3 to 10-membered mono-, bi- or spirocyclic cycloalkyl ring, where the ring system is optionally substituted by one or more of the following substituents: F, CF 3 , (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, CO(R53), and hydroxyl;

R50, R51, R52, and R53

are each independently H or (C 1 -C 6 )-alkyl;

and the physiologically compatible salts thereof, excluding the compound 4-(1-hydroxy-cyclobutylmethoxy)-N—((S)-6-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydronaphthalen-2-yl)benzamide.

2. The compound as claimed in claim 1 , in which

A is selected from the group consisting of

each A optionally substituted by one or more of the substituents H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, N(R43)(R44), SO 2 —CH 3 , CON(R45)(R46), N(R47)CO(R48), and CO(R49).

3. The compound as claimed in claim 1 , in which L2 is a bond, O or C(R51)(R52)O.

4. The compound as claimed in claim 1 , in which

B is a 3 to 6-membered cycloalkyl ring, where the ring system is optionally substituted by one or more of the following substituents: F, (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 -alkyl, and hydroxyl.

5. The compound as claimed in claim 1 , in which

R1 is (C 1 -C 8 -alkyl, (C(R10)(R11)) q -R12, or (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl; and

R2 is H, (C 1 -C 8 )-alkyl, (C(R10)(R11)) q -R12, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, CO—(C 1 -C 8 )-alkyl, CO—O(C 1 -C 8 )-alkyl, or CO(C(R13)(R14)) r N(R16)(R17).

6. The compound as claimed in claim 1 , in which

R1 is (C(R10)(R11)) q -R12;

R2 is H or (C 1 -C 6 )-alkyl;

q is 1, 2, 3, or 4;

R10 and R11

are each independently H or (C 1 -C 6 )-alkyl;

R12 is a 3-12-membered mono-, bi- or spirocyclic saturated ring containing one to three heteroatoms from the group of N, O and S, and the 3-12-membered ring optionally containing further substituents selected from F, OH, CF 3 , CN, OCF 3 , oxo, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, N(R31)(R32), and SO 2 (C 1 -C 6 )-alkyl.

7. The compound as claimed in claim 1 , in which

R1 and R2, together with the nitrogen atom to which they are bonded, form a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, optionally includes 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system is optionally substituted by F, CF 3 , (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 6 )-alkyl, oxo, CO(R18) or hydroxyl.

8. The compound as claimed in claim 1 , in which

R3, R4, and R5 are each H; and

R6, R6′, R7, R7′, R7″, and R7″′ are each H.

9. The compound as claimed in claim 1 , characterized by the formula II

in which the variables R1, R2, L1, R3, R4 and R8 are each as defined in claim 1 and

Y is CR or N;

R, R′, R″, and R″′

are each independently H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 ), alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, N(R43)(R44), SO 2 —CH 3 , CON(R45)(R46), N(R47)CO(R48), or CO(R49);

L2 is CH 2 O;

B is (C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 6 )-alkyl, or a 3 to 6-membered cycloalkyl ring, where the ring system is optionally substituted by one or more of the following substituents: F, (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, and hydroxyl.

10. The compound as claimed in claim 1 , characterized by the formula III

in which R8 is H or (C1-6)-alkyl;

R and R′ are each independently H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 ), alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, N(R43)(R44), SO 2 —CH 3 , CON(R45)(R46), N(R47)CO(R48), or CO(R49);

B is (C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 6 )-alkyl, or a 3 to 6-membered cycloalkyl ring, where the ring system is optionally substituted by one or more of the following substituents: F, (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, and hydroxyl

R1 is (C(R10)(R11)) q —R12;

R2 is H or (C 1 -C 6 )-alkyl;

q is 1, 2, 3, or 4;

R10 and R11

are each independently H or (C 1 -C 6 )-alkyl; and

R12 is a 3-12-membered mono-, bi- or spirocyclic saturated ring which contains one to three heteroatoms from the group of N, O and S, and the 3-12-membered ring optionally contains further substituents selected from F, OH, CF 3 , CN, OCF 3 , oxo, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, N(R31)(R32) and SO 2 (C 1 -C 6 )-alkyl.

11. The compound as claimed in claim 1 , characterized by the formula IIIa

in which R8 is H or (C1-C6)-alkyl;

B is (C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 6 )-alkyl, or a 3 to 6-membered cycloalkyl ring, where the ring system is optionally substituted by one or more of the following substituents: F, (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, and hydroxyl;

R1 is (C(R10)(R11)) q —R12;

R2 is H or (C 1 -C 6 )-alkyl;

q is 1, 2, 3, or 4;

R10 and R11

are each independently H or (C 1 -C 6 )-alkyl; and

R12 is a 3-12-membered mono-, bi- or spirocyclic saturated ring which contains one to three heteroatoms from the group of N, O and S, and the 3-12-membered ring optionally containing further substituents selected from such as F, OH, CF 3 , CN, OCF 3 , oxo, 0-(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, N(R31)(R32) and SO 2 (C 1 -C 6 )-alkyl.

12. The compound as claimed in claim 1 , characterized by the formula IV

in which R2, R8, L2, A and B are each as defined in claim 1 and

n is 1 or 2;

R1′ is H, methyl or ethyl.

13. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically suitable carrier.

14. The pharmaceutical composition according to claim 13 , further comprising one or more antidiabetics.

15. The pharmaceutical composition according to claim 13 , further comprising one or more lipid modulators.

16. The pharmaceutical composition according to claim 13 , further comprising one or more antiobesity agents.

17. A process for preparing the pharmaceutical composition according to claim 13 , comprising mixing an active ingredient with a pharmaceutically suitable carrier and converting said mixture to a form suitable for administration.